Lp(a) is a kind of lipoproteins. It is considered that apolipoprotein (a) (apo (a)) is attached, by an S--S bond, to apo B-100 which surrounds molecules analogous to low density lipoprotein (LDL), thereby circularly surrounding the particles (refer to Arteriosclerosis, 24(7.8), 369-374(1996)). As a result of investigation continued since the existence of Lp(a) was reported [Acta. Pathol. Microbiol. Scand., 59, 369-382(1963)], Lp(a) is presumed to participate in the onset of ischemic cardiac diseases or cerebral infarction. When a patient has suffered from hyperlipoproteinemia of Lp(a) in spite of being free from a factor of hypercholesterolemia, diabetes, hypertension or the like, the onset ratio of an arteriosclerotic disease is rec ognized to become markedly as one of risk factors which may cause arteriosclerosis. For example, it is reported that when the total cholesterol level in blood is normal but the Lp(a) level is high, the onset ratio of a coronary artery disease becomes high (New England J. Med., 322(1990)). In addition, it is known that the level of Lp(a) is high in Buerger's disease which is a non-arteriosclerotic lesion, which suggests the relation between them [Arteriosclerosis, 24(7.multidot.8), 369-374(1996)]. In most cases, occurrence of hyperlipoproteinemia of Lp(a) has been found to be governed by the genetic character of the patient.
In recent years, Lp(a) is found to have a fundamental structure similar to that of plasminogen and is therefore presumed to participate in the suppression of the coagulation fibrinolytic system, thus having thrombus forming action [Nature, 330, 132-137(1987)]. In addition, Lp(a) is presumed to participate in the constriction of an injured tissue in the lumen of a blood vessel by inhibiting activation of TGF-.beta. and accelerating the proliferation of endothelial cells within the blood vessel and migration of smooth muscle cells from the media into the inner membrane [J. Cell. Biol., 113, 1439-1445(1991)].
From such findings, there was a demand for the development of an agent capable of significantly lowering the Lp(a) level in blood as a remedy or preventive for arteriosclerotic diseases free from a factor of hypercholesterolemia, diabetes, hypertension or the like, a remedy or preventive for Buerger's disease, and also as anti-thrombosis and a remedy or preventive for reconstriction after PTCA.
Most of the conventional anti-hyperlipidemia agents are reported to have no apparent effects for lowering the Lp(a) level in blood. Only a nicotinic acid derivative is regarded to be effective (ARTERIOSCLEROSIS, 10(5), 672-679(1990)), but it is insufficient as a pharmaceutical, because administration at a high dose (1.5 to 2.0 g/body) is required owing to its markedly weak action and in addition, side effects such as suffusion appear.
An object of the present invention is therefore to provide an Lp(a) lowering agent which can significantly lower the Lp(a) level, is almost free from side effects and exhibits effects at a low dose. Another object of the present invention is to provide an agent for suppressing the formation of apo(a) which constitutes such Lp(a).